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Ashish Kamat: Hello, and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat from MD Anderson Cancer Center in Houston, Texas. And we are joined today by Professor Evanguelos Xylinas, who is Head of the Urologic Oncology Unit at the Paris University and the Bichat-Claude Bernard Hospital. Professor Xylinas, of course, needs no introduction. He is active in many different working groups and guidelines' panels and then publishes extensively in urothelial cancer. And today, he's going to talk to us about systemic therapies for localized upper tract urothelial carcinoma. Evanguelos, the stage is yours.

Evanguelos Xylinas: Hello, and thank you for the kind invitation and the opportunity to discuss systemic therapies for localized upper tract urothelial carcinoma, which I think is a hot and interesting topic. So, the POUT trial has established adjuvant chemotherapy, platinum-based adjuvant chemotherapy as a new standard of care treatment in high-risk localized upper tract disease treated with radical nephroureterectomy. It was a phase three randomized controlled trial in kidney patients pT2-pT4 and/or the N+ plus, but had been treated with surgery and were randomized to receive either surveillance or platinum-based chemotherapy based on the GFR, estimated GFR. As you know, the POUT trial met its primary endpoint, which was disease-free survival with a hazard ratio of 0.45 and, therefore, leading to adjuvant chemotherapy being incorporated in national and international guidelines as the new standard of care after surgery for these upper tract diseases.

However, I had some limitations to point out, and the first was the accrual. As you can see here, overall 261 patients were enrolled in 57 centers in five years time frame, meaning that less than one patient per center per year was enrolled in the study, showing that patients were selected in the POUT trial.

Second, as I mentioned earlier, the primary endpoint was disease-free survival, and unfortunately, not overall survival. That questions the potential benefit of deferred chemotherapy at the time of relapse, compared to adjuvant chemotherapy, which was the purpose of this study. And we know from the plots, which are urothelial carcinoma of the bladder, that immediate versus deferred chemotherapy has not shown any benefit, meaning that immediate chemotherapy was superior to surveillance in terms of progression-free survival in a trial back in 2015 from the EORTC. But, unfortunately, it was not superior to deferred chemotherapy in terms of overall survival. So, the question is, adjuvant chemotherapy does better today but does it do better than deferred chemotherapy at the time of relapse?

The third point I wanted to highlight today was that when you look at the disease features of the patients included, approximately 9% of the patients had pN+ disease, meaning lymph node involvement. There were not any patients having pNx disease, meaning no lymph node dissection was performed, which is quite common in upper tract disease in up to 50% of the cases based on the retrospective study. These questions on the lymph node dissection performed in the POUT trial and may have impacted oncological outcomes as in this study, you compared surgery plus adjuvant chemotherapy versus surgery plus surveillance, meaning that surgery may have played a role in the oncological outcomes of either group.

Moreover, when we look at patient features, you can see here that overall, 63.8% of the patients were cisplatin eligible based on renal function, which is really high compared to classical retrospective studies of daily practice, showing that prior to RNU, 50% of the patients having an eGFR below 60, which is usually the cutoff chosen to be eligible for cisplatin-based chemotherapy. And after RNU, usually, only 25% of the patients are eligible for cisplatin-based chemo based on the same cutoff of 60. Meaning that once again, in this trial patients were selected and therefore had the higher eligibility to cisplatin-based chemo.

Finally, when you look at what treatments really patients received in this trial, so the chemotherapy regimen only, approximately 68% received the planned treatment, and up to 13% of the patients switched during the treatment from cisplatin-based to carboplatin-based chemotherapy. And one can argue that carboplatin is not as efficient as a chemotherapy regimen as cisplatin-based in terms of urothelial carcinoma treatment. Once again, it was not the purpose of the study. So we cannot conclude on the efficacy of either carboplatin or cisplatin-based regimens. So if we put all of this together and we put the arguments for neoadjuvant or adjuvant therapies and chemotherapy, in particular, the neoadjuvant settings allow for a patient to be more fit, to be more eligible to cisplatin, based on renal function because of the interim class of renal function due to surgery after radical nephro-U.  However, the data are more like proof of concept, with no strong level one evidence.

And another drawback is that the pathological evidence of the tumor is weak because the evaluation in the pre-operative workout is based on ureteroscopic biopsy or a combination of CT plus urine cytology, and it's not as easy as we would want.  In comparison to the adjuvant setting, the patient is a little bit less fit based on surgery, and of course, less eligible for cisplatin-based chemo. The evidence of course is strong due to the POUT phase three trial, and so level one evidence. And of course, the selection of patients is based on the pathological evidence of tumor on the radical nephroureterectomy specimen. And so this is a more strong data on the aggressiveness of the disease. Do we have any data on neoadjuvant chemo? So we have, we are fortunate to have one phase two trial, which was a feasibility trial from the United States published last year in The Journal of Urology.

It was a two-arm study and the most important study was the Arm A group of 29 patients that had received accelerated aMVAC every 14 days for four cycles and showed a complete response for ypT0 of 14% and a downstaging to nonmuscle invasive disease up to 62%. So the feasibility of the aMVAC prior to RNU was demonstrated with some data. We are as a national French group evaluating in this study named iNDUCT sponsored by AFU and GETUG, we are evaluating a combination of immune checkpoint inhibitors and chemotherapy prior to surgery in these high-risk upper tract diseases, nonmetastatic, of course, and we are going to choose the patients and select the patients based on UC histology. So either high-grade ureteroscopic biopsy or a combination of high-grade urine cytology, plus infiltrative aspect on the CT imaging prior to surgery, and patients are going to receive four cycles of this combination of treatment.

And we are going to evaluate the response based on pathological complete response or ypT0, and we expect to have more than 15% of the patients having pT0 disease after surgery in this single-arm, open-label, phase two study, which I'm happy to coordinate with professor DuPre And you already know. So as you can see here, upper tract disease is complex.  Adjuvant chemotherapy has shown some level one evidence establishing it as the new standard of care after surgery, but neoadjuvant treatment chemotherapy and probably immune checkpoint inhibitors are coming also in this setting of upper tract disease. And I think this is quite interesting and I'm looking forward to a discussion with professor Kamat.

Ashish Kamat: So this was great. Thank you so much for covering the topic in such a concise manner. You know, one of the things that we often are faced with is we have a paucity of phase three studies. And then of course, when we have a phase three study that reads out, we have to obviously recognize the effort that goes into it from the investigators, the patients, and the results. But it's always, again, important to look at the study like you did, and evaluate it from a real-world perspective because what we see in clinical studies is not the same as being translated into the real world. So let me ask you a very practical question. When you see a patient in the clinic today, Evangelos, with upper tract disease, how do you counsel the patient on the pros and cons of perioperative systemic chemotherapy?

Evanguelos Xylinas: I say, of course, I fully agree that extrapolating data from clinical trials to daily practice is not always easy. So when I see a patient, I could have shown a video of a CT scan of the patient with a big upper tract disease. And the question is always, do I do neoadjuvant chemo, and then I do surgery?  Or do I start with surgery? And if he has aggressive features as shown in the POUT trial, I do adjuvant chemo. I think we would have to stick with the guidelines. And despite, I think tomorrow neoadjuvant chemo could be the standard of care. As of today, the standard of care is surgery and in selected patients based on pathological specimen results to give adjuvant chemo in the muscle-invasive disease, locally advanced or left node involvement. So I would advise surgery to stop.

Ashish Kamat: So I'm glad you said that because again, you know, you pointed out the flaws in the POUT study, but recognizing that it is level one evidence and it is in the guidelines is very important. And, and I'm glad you said that because our audience, you know, needs to hear that. The second question for you, where do you feel the field has already evolved and is heading as far as being able to select patients for therapy, either neoadjuvant or surgery or adjuvant based on current molecular markers, you know, either gene expression profiling or, immunohistochemistry?  Do you use any of that in your practice?

Evanguelos Xylinas: So of course, molecular subtyping is trying to achieve to be in daily practice. We look at that for urothelial carcinoma of the bladder. We don't look at that yet for upper tract disease.  But because as we already know, these are quite common diseases, disparate twins was the name in a review from the Daily Green  years ago? And I think they are common, but they are really separate as well. So I cannot say, but we do use biology and molecular subtyping in upper tract disease. I can say that for the iNDUCT trial, we're going to do an auxillary phase 2 study. So in order to look at these molecular subtypes and to see if there is some sort of correlation with response to the combination of chemotherapy and immune checkpoint inhibitors.

Ashish Kamat: Right. You know, and again, there was recently a publication that came out from Billy Kim's group that suggested that the whole story with the FGFR3 upper tract tumors not being as responsive to IO is not actually true when you look at it in the real world. So I agree with you, you know, we need to wait for validation of the molecular subtypes and the other correlations before making any clinical decisions. So, you know, this has been a great discussion.  In the closing minute or two, I will hand the stage over to you and ask you to highlight some key points of systemic therapies for our audience that you want to leave them with, some take-home messages.

Evanguelos Xylinas: Yes. Thank you. So take-home messages. I think that the upper tract field is fortunate to have level one evidence with the POUT trial, highlighting the benefits associated with adjuvant chemotherapy for muscle-invasive locally advanced and lymph node involvement diseases after surgery. And as of today, I think, as we said before, it is the new standard of care. This type has shown benefit only in disease-free survival and not overall survival and with all the shortcomings that come with it. I know that in the next years the field is going to evolve with immune checkpoint inhibitors, of course, and also FGFR inhibitors, which we did not have the time to discuss today, but are also coming in this field of upper tract disease, which has shown to have more mutations, more genetic and mobilities of GFR pathway than the urothelial carcinoma of the bladder. So I think these are also exciting pathways and exciting targeted therapies coming in this field. So looking forward to these fields moving and in the interest of our patients.

Ashish Kamat: All right, thank you once again, for taking the time and spending it with us today, it is always a pleasure to chat with you. Hopefully, we will get to see each other in person sometime soon.

Evanguelos Xylinas: Thank you very much.